Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19
Authors: Teluguakula Narasaraju, Amita Krishnappa, Marko Radic, Vincent T.K. Chow
Journal: Annals of Internal Medicine (2023)

LettersFebruary 2023Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19FREETeluguakula Narasaraju, PhD, Amita Krishnappa, MD, Marko Radic, PhD, Vincent T.K. Chow, MD, PhDTeluguakula Narasaraju, PhDAdichunchanagiri Institute of Medical Sciences, Karnataka, India, Amita Krishnappa, MDAdichunchanagiri Institute of Medical Sciences, Karnataka, India, Marko Radic, PhDUniversity of Tennessee Health Science Center, Memphis, Tennessee, Vincent T.K. Chow, MD, PhDNational University of Singapore, Kent Ridge, SingaporeAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L22-0455 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR: The ACTIV-3/TICO (Accelerating COVID-19 Therapeutic Interventions and Vaccines/Therapeutics for Inpatients with COVID-19) Study Group (1) analyzed the efficacy and safety of ensovibep. This designed ankyrin repeat protein inhibits the interaction of SARS-CoV-2 spike protein with its host receptor, angiotensin-converting enzyme 2. This randomized controlled trial was a follow-up of earlier studies that showed antiviral activity of ensovibep in a hamster model of COVID-19 as well as reduced hospitalizations and improved clinical outcomes in outpatients with mild to moderate COVID-19. In contrast to those findings, the ACTIV-3/TICO Study Group showed that administration of ensovibep in severely ill patients hospitalized with COVID-19 did not exhibit any protection. This trial was prematurely discontinued because it failed early futility assessment and could not establish the power of the primary outcome in patients hospitalized with COVID-19. The study design has several shortcomings.First, this trial failed to establish the proof of concept of antiviral efficacy of ensovibep.Second, randomly assigning and blinding participants provide an unbiased approach; however, the 7 ordinal pulmonary or pulmonary-plus outcome scales used are unlikely to provide any direct correlation or clinical signatures specific for ensovibep-mediated effects, including lung viral loads or virus-inflicted alveolar–epithelial cytopathic injury.Third, combining remdesivir with ensovibep in the treatment regimen is unlikely to establish any beneficial effects.Finally, the lack of realistic data on viral replication and kinetics at the onset of treatment raises questions about the rationale for this clinical trial. Several clinical trials that evaluated combinations of monoclonal antibodies (for example, tixagevimab–cilgavimab or sotrovimab and BRII-196 plus BRII-198) in patients hospitalized with COVID-19 on the basis of ordinal outcome scales similarly yielded inconsistent findings and fell short of proving their efficacy in these patients (2, 3).When drugs targeting virus entry or replication in the lungs are evaluated, the inclusion of additional criteria to support the proof of concept is essential. Viral titers in nasopharyngeal or oropharyngeal samples unfortunately do not correlate well with viral loads in the deeper lungs, and use of invasive methods to collect lung samples may not be possible in patients hospitalized with COVID-19. Instead, measuring plasma viral RNA may be a better indicator to determine the antiviral effects of ensovibep or monoclonal antibodies in these patients (4). In addition, markers of alveolar epithelial injury such as podoplanin (a marker of alveolar type I epithelium) and surfactant protein C (a marker of alveolar type II epithelium) (5) in the plasma or sputum may represent virus-inflicted alveolitis in the lungs. As such, evaluating COVID-19 pathophysiology and clinical outcomes on ordinal outcome scales must be substantiated by more prudent methods that are relevant to drug target–specific signatures.References1. ACTIV-3/TICO Study Group. Efficacy and safety of ensovibep for adults hospitalized with COVID-19. A randomized controlled trial. Ann Intern Med. 2022;175:1266-74. [PMID: 35939810] doi:10.7326/M22-1503 LinkGoogle Scholar2. ACTIV-3-Therapeutics for Inpatients with COVID-19 (TICO) Study Group. Tixagevimab–cilgavimab for treatment of patients hospitalised with COVID-19: a randomised, double-blind, phase 3 trial. Lancet Respir Med. 2022;10:972-84. [PMID: 35817072] doi:10.1016/S2213-2600(22)00215-6 CrossrefMedlineGoogle Scholar3. ACTIV-3/Therapeutics for Inpatients with COVID-19 (TICO) Study Group. Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial. Lancet Infect Dis. 2022;22:622-35. [PMID: 34953520] doi:10.1016/S1473-3099(21)00751-9 CrossrefMedlineGoogle Scholar4. Jacobs JL, Bain W, Naqvi A, et al. Severe acute respiratory syndrome coronavirus 2 viremia is associated with coronavirus disease 2019 severity and predicts clinical outcomes. Clin Infect Dis. 2022;74:1525-33. [PMID: 34374761] doi:10.1093/cid/ciab686 CrossrefMedlineGoogle Scholar5. Ashar HK, Pulavendran S, Rudd JM, et al. Administration of a CXC chemokine receptor 2 (CXCR2) antagonist, SCH527123, together with oseltamivir suppresses NETosis and protects mice from lethal influenza and piglets from swine-influenza infection. Am J Pathol. 2021;191:669-85. [PMID: 33453177] doi:10.1016/j.ajpath.2020.12.013 CrossrefMedlineGoogle Scholar Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Adichunchanagiri Institute of Medical Sciences, Karnataka, IndiaUniversity of Tennessee Health Science Center, Memphis, TennesseeNational University of Singapore, Kent Ridge, SingaporeDisclosures: Authors have reported no disclosures of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L22-0455. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoEfficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19 Eleftherios Mylonakis , Christina Barkauskas , Garyfallia Poulakou , Barnaby E. Young , and Metrics Current IssueFebruary 2023Volume 176, Issue 2KeywordsCOVID-19Clinical trialsCritical careData and safety monitoring boardsHealth statisticsHospital medicineHospitalizationsInfectious diseasesSafetyVeteran care ePublished: 21 February 2023 Issue Published: February 2023 Copyright & PermissionsCopyright © 2023 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...